The purpose of this project is to develop and apply new hetero- and carbocyclization reactions in the total synthesis of natural products. These new reactions will considerably simplify existing syntheses of biologically active compounds and, in addition, provide routes to previously unsynthesized compounds. One reaction that will be studied is a version of the intramolecular Diels-Alder reaction. This research will be used in the total synthesis of compactin, a compound that causes a marked decrease in serum cholesterol in rats and other animals by inhibiting the rate-limiting enzyme, HMG-CoA reductase, in the cholesterol biosynthetic pathway. Since high serum cholesterol may be one of the major causes of atherosclerosis, it is hoped that this hypocholesterolemic agent will be useful in the treatment of this disease. A second reaction to be applied in synthetic schemes is a novel ring-forming Claisen rearrangement. The proposed enantiospecific synthesis of gabaculine, a compound which inhibits an enzyme that is involved in the metabolism of gamma-aminobutyric acid (GABA), utilizes this reaction in a key step. It is expected that gabaculine will become an extremely useful tool for investigating GABA, an inhibitory transmitter substance in the nervous system. A novel, stereospecific route to the antitumor pseudoguaianolides and analogs thereof will also arise upon application of this methodology. Further extension of the ring-forming Claisen rearrangement will result in novel routes to the medicinally important tetrahydropyridine and isoquinuclidine classes of compounds, eg, catharanthine, a component of the clinically important antitumor agents vincristine and vinblastine, and a novel route to cycloalkanes of various ring sizes which will be useful for the synthesis of the antibiotic, antitumor class of tricyclopentanoid sesquiterpenes and biologically active small ring natural products.